Terapia della fase stabile della BPCO:
farmacoterapia
Dr. Claudio Micheletto – Legnago (VR)
…..
GOALS FOR TREATMENT OF STABLE COPD
Reduce symptoms
•Relieve symptoms
•Improve exercise tolerance
•Improve health status
Reduce risk
•Prevent disease progression
•Prevent exacerbations
•Reduce mortality
Am J Resp Crit Care 2013
CLASSE
FARMACO
CARATTERISTICA
Anticolinergici a lunga
durata d’azione (LAMA)
Tiotropio bromuro
Glicopirronio
Aclidinium
Durata di azione 24 ore
Durata di azione 24 ore
Durata di azione 12 ore
Β2 agonisti a lunga durata
d’azione (LABA)
Salmeterolo
Formoterolo
Indacaterolo
Durata di azione 12 ore
Durata di azione 12 ore
Durata di azione 24 ore
Combinazioni precostituite Salmeterolo-fluticasone
LABA + CSI
Formoterolo-budesonide
Durata di azione 12 ore
Inibitore delle
fosfodiesterasi-4
Per os
Durata di azione 24 ore
Roflumilast
CLASSE
FARMACO
CARATTERISTICA
Β2 agonisti a breve durata
d’azione (SABA)
Salbutamolo
Terbutalina
Fenoterolo
Rapido esordio della
broncodilatazione, durata
di azione 4-6 ore
Anticolinergici a breve
durata d’azione (SAMA)
Ipratropio bromuro*
Ossitropio bromuro*
Esordio meno rapido, ma
durata un po’ più lunga dei
SABA (4-6 ore)
Metilxantine
Teofilline orali a lento
rilascio
Finestra terapeutica
ristretta. Farmaci
aggiuntivi nei pazienti più
gravi
LABA: long acting beta2 agonist
LAMA: long acting muscarinic
antagonist
SABA: short acting beta2 agonist
SAMA: short acting muscarinic
antagonist
CSI: corticosteroidi inalatori
* Disponibili solo per aerosol
La scelta terapeutica deve essere adeguata per la
singola persona e guidata dalle caratteristiche e
dalla gravità del quadro clinico considerato nel suo
insieme
di
sintomi,
funzione
respiratoria,
complicanze, comorbilità e delle peculiarità
individuali (fenotipo) della persona che ne è affetta.
Am J Resp Crit Care Med 1995
The COPD dilemma
COPD is defined by the presence of airflow
limitation that is not fully reversible, and its
treatment is mostly guided by the severity of this
limitation.
Severity
Postbrochodilator
FEV1/FVC
FEV1 % pred
At risk
>0.7
80
Mild COPD
0.7
80
Moderate COPD
0.7
50–80
Severe COPD
0.7
30–50
Very severe COPD
0.7
<30
Han AJRCC 2010
The COPD dilemma
it is now widely recognized that COPD is a complex
syndrome
with
pulmonary
and
extrapulmonary
components. Importantly, significant heterogeneity exists
with respect to clinical presentation, physiology, imaging,
response to therapy, decline in lung function, and survival.
Han AJRCC 2010
The COPD dilemma
4
(C)
(D)
≥2
3
1
2
(A)
(B)
1
RISK
Exacerbation history
RISK
GOLD classification of Airflow Limitation
There is consensus that FEV1 by itself does not adequately
describe the complexity of the disease and that FEV1
cannot be used in isolation for the optimal diagnosis,
assessment, and management of the disease.
0
mMRC 0-1
mMRC ≥ 2
CAT < 10
CAT ≥ 10
Symptoms
Vestbo J, et al. AJRCCM 2013
Vestbo J, et al. AJRCCM 2013
GOLD 2013
Manage Stable COPD: Pharmacologic Therapy
Patient
Recommended
First choice
Alternative choice
Other Possible
Treatments
A
SAMA prn
or
SABA prn
LAMA
or
LABA
or
SABA and SAMA
Theophylline
B
LAMA
or
LABA
LAMA and LABA
SABA and/or SAMA
Theophylline
ICS + LABA
or
LAMA
LAMA and LABA or
LAMA and PDE4-inh. or
LABA and PDE4-inh.
ICS + LABA
and/or
LAMA
ICS + LABA and LAMA or
ICS+LABA and PDE4-inh. or
LAMA and LABA or
LAMA and PDE4-inh.
C
D
SABA and/or SAMA
Theophylline
Carbocysteine
SABA and/or SAMA
Theophylline
SAMA: antimuscarinici a breve durata d’azione; SABA: β2-agonisti a breve durata d’azione; p.r.n.: all’occorrenza (pro re nata);
LAMA: antimuscarinici a lunga durata d’azione; LABA: β2-agonisti a lunga durata d’azione; ICS: corticosteroidi per via inalatoria; PDE-4: fosfodiesterasi-4
Summary handout, Revised GOLD 2011 www.goldcopd.org/guidelines-gold-summary-2011.html
The identification and subsequent grouping of key elements
of the COPD syndrome into clinically meaningful and useful
subgroups (phenotypes) that can guide therapy more
effectively is a potential solution of the dilemma
Han KM, et al. Am J Respir Crit Care Med 2010; 182, 598-564
Phenotypes – an operational definition
‘‘a single or combination of disease attributes that
describe differences between individuals with
COPD as they relate to clinically meaningful
outcomes (symptoms, exacerbations, response to
therapy, rate of disease progression, or death).’’
Han KM, et al. Am J Respir Crit Care Med 2010; 182, 598-564
GOLD 2013
Efficacy of Tiotropium in COPD Patients with
FEV1 ≥ 60% participating in the UPLIFT® Trial - SGRQ~40
Tashkin DP, et al J COPD 2012
Efficacy of Tiotropium in COPD Patients with
FEV1 ≥ 60% participating in the UPLIFT® Trial
Tashkin DP, et al J COPD 2012
GOLD Stage II: Exacerbations
Tiotropium
(n=1384)
Control
(n=1355)
Ratio
(95% CI)
P-value
Time to first
exacerbation
(month)
23.1
(21.0, 26.3)
17.5
(15.9, 19.7)
0.82
(0.75, 0.90)*
<0.0001*
Mean number of
exacerbations/pt
yr (95% CI)
Mean number of
hospitalizations
for exacerbations/
pt yr (95% CI)
0.56
(0.52, 0.60)
0.70
(0.65, 0.75)
0.80
(0.72, 0.88)†
<0.0001†
0.08
(0.07, 0.09)
0.10
(0.08, 0.12)
0.80
(0.63, 1.03)†
0.082†
†Rate
*Hazard ratio (control vs. tiotropium) and P-value were estimated using Cox regression.
ratio (tiotropium/control) and P-value were estimated using the Poisson with Pearson overdispersion
model adjusting for treatment exposure.
Decramer et al. Lancet 2009; 374: 1171-78
Indacaterolo 300 µg
Indacaterolo µg 150
Tiotropio
•†††
•†††
•220
•200
•†††
•180
•†††
•160
•FEV1 (ml)
•***
•150
•†††
•***
•120
•140
•***
•130
•***
•190
•***
•180
•†††
•***
•160
•***
•160
•***
•140
•***
•110
•***
•120
•***
•120
•MCID
•90
•100
•80
•**
•50
•60
•40
•20
•0
•5
•15
•30
•60
•Tempo dopo la dose (min)
**p<0,01; ***p<0,001 vs placebo. †††p<0,05 vs tiotropio
Aumenti rispetto al basale a 5 min post-dose: 60 ml (4,4%) con tiotropio, 130 ml (9,7%) con
indacaterolo 150 µg
e 140 ml (10,2%) con indacaterolo 300 µg.
Vogelmeier et al. Respiratory Research 2010
Placebo
Indacaterolo 150 µg o.d.
3.0
Tiotropio 18 µg o.d.
Indacaterolo 300 µg o.d.
†
2.0
***
2,13
1,95
2,38
***
2,27
2,41
***
2,58
1 punto
***
1 punto
TDI focal score
***
***
1,40
1,20
1.0
0
Settimana 12
Settimana 26
•Media dei minimi quadrati (LSM).. ***p<0.001 vs placebo; +p<0.05 vs tiotropio BRACCIO IN APERTO
•Differenza ≥1 = miglioramento clinicamente significativo del TDI score
Donohue et al. Am J Respir Crit Care Med 2010
Punteggio totale SGRQ
51,0
MIGLIORAMENTO
Differenza -2,1
(p<0,001)
Pazienti (%) con variazione
clinicamente importante del
punteggio totale SGRQ
47,0
Odds ratio 1,43
(p<0,001)
43,0
39,0
35,0
SGRQ = St. George’s Respiratory Questionnaire (questionario respiratorio St.
George)
L.J Dunn , R Buhl et al. Studio Intensity
Aclidinium improves trough FEV1:
150
Placebo BID
Aclidinium 400 µg BID
Change from baseline
in trough FEV1 (mL)
100
***
***
***
***
***
***
50
128 mL
0
-50
-100
0
4
8
12
16
20
24
Treatment week
***p0.001 vs placebo
Jones et al, Eur Respir J 2012
Aclidinium reduces COPD exacerbation
(any severity) rates (24 weeks)
1.6
COPD exacerbations
(/pt/year)
Placebo BID
Aclidinium 400 µg BID
1.39
1.2
29%
0.98*
0.8
0.60
0.4
0.40*
33%
0.0
Healthcare Resource
Utilization criteria
*p<0.05 vs placebo
EXACT
criteria
Jones et al, CHEST 2012
Nelle persone in regolare trattamento farmacologico,
valutare ad ogni visita programmata:
• la corretta e regolare assunzione della terapia
• la valutazione dei sintomi ed in particolare, la
tolleranza all’esercizio fisico e la dispnea da sforzo
• le modificazioni della funzione polmonare non
solo in termini di FEV1 ma anche di altri parametri
come i volumi polmonari e la DLCO
• la frequenza con la quale la persona ricorre a
broncodilatatori a breve durata d’azione come
supporto occasionale
• la frequenza
riacutizzazione
e
gravità
degli
episodi
di
• la frequenza e la durata degli episodi di
ospedalizzazione
• la frequenza e la gravità
collaterali e/o avversi
di eventuali eventi
GOLD 2013
Kaplan–Meier Curves for the Primary and Selected Secondary Outcomes.
•
Vogelmeier C et al. N Engl J Med 2011;364:1093-1103
These results show that, in patients
with moderate-to-very-severe COPD,
tiotropium is more effective than
salmeterol in preventing
exacerbations.
GOLD 2013
JA van Noord, et al . Eur Resp J 2005; 26: 214-22.
Dual bronchodilation with QVA149:
the SHINE study
2/3 moderati; quasi 80% no riac. Sintomatici per entry. SGRQ >40
Bateman et al Eur Respir J. 2013
Pre-dose trough FEV1 was significantly higher with QVA149 vs
glycopyrronium and tiotropium at all assessments
1.20
QVA149
Glycopyrronium
Tiotropium
Trough FEV1(L)
1.10
1.00
0.90
0.80
0.70
0.60
0
0
4
12
26
38
52
64
Weeks
Differences between QVA149 and glycopyrronium and tiotropium were statistically significant (p<0.0001) at each assessment during
the treatment period. Data are least squares means ±SE
Wedzicha JA, et al. Lancet Resp Med 2013 1 (3): 199-209
Rate reduction of COPD exacerbations
QVA149
COPD Exacerbations (annualized rate)
5
4.5
4
3.5
Glycopyrronium
Tiotropium
0.84*
(0.75, 0.95)
0.86**
(0.78, 0.94)
0.85††
(0.77, 0.94)
0.85†
(0.75, 0.96)
3
0.90‡
(0.79, 1.02
2.5
2
0.88§
(0.77, 0.99)
1.5
1.16¶
(0.84, 1.61)
0.81||
(0.60, 1.10)
1
0.5
0
Mild exacerbations
Moderate/severe
exacerbations
Severe exacerbations
All exacerbations
Values are rate reduction (95% CI); n numbers per treatment group: QVA149 n=729; glycopyrronium n=739; tiotropium n=737.
*p=0.0052,†p=0.0072,‡p=0.096,§p=0.038,¶p=0.36,||p=0.18,**p=0.0017,††p=0.0012.
Wedzicha JA, et al. Lancet Resp Med 2013 1 (3): 199-209
FEV1 AUC0–12h at Week 26
No riac per inclusione ; >80% moderati..
∆=138 mL, p<0.0001
FEV1 AUC 0–12h ( L)
1,8
1,7
1,6
1,5
1,56
1.70
1,4
Fluticasone/salmeterol
500/50 μg
Values are least-squares mean ± standard error
QVA149
110/50 μg
Vogelmeier CF, et al. Lancet Resp Med. 2012
Mean SGRQ-C total score
Improvement
Data are LSM (SE); Mean difference in SGRQ-C total score for QVA149 versus SFC at Week 26 was –1·24 (p=0·245); SGRQ=St
George’s Respiratory Questionnaire; LSM=least squares mean; SE=standard error; SFC=salmeterol/fluticasone
Vogelmeier CF, et al. Lancet Resp Med. 2012
GOLD 2013
number/patient/year
In the TRISTAN study, FP/Salm combination
reduced the number of severe exacerbations
1.5
1.30
1.04
1.05
**
**
SAL50
FP500
1
0.97
*
0.5
0
PLA
* p< 0.001 vs PLA
** p = 0.003 vs PLA
SFC50/500
Calverly et al, Lancet 2003
TORCH Study: additional effect of
salmeterol/fluticasone vs both monotherapies
FEV1≤60%
Calverley MD, et al. New Eng J Med 2007, Vol.356 (8): 775-210
TORCH. SGRQ Total Score
Corrected mean change in SGRQ total score
3
Placebo
2
1
SALM
*
0
–1
†
FP
††
SALM/FP
–2
–3
–4
–5
0
Number of 1149
1148
subjects
1155
1133
24
48
854
906
942
941
781
844
848
873
72
96
Time (weeks)
*p = 0.057 vs placebo; †p < 0.001 vs placebo;
726
807
807
814
††p
675
723
751
773
120
156
635
701
686
731
569
634
629
681
< 0.001 vs placebo, SALM and FP; vertical bars are standard errors
Calverley et al, NEJM 2007
N. medio riacutizzazioni/paziente/anno
Bud/Form: reduction of exacerbations
*
1.8
2.0
1.8
1.6
*
1.9
1.6
1.4
1.4
1.2
1.2
1.0
1.0
0.8
0.8
0.6
0.6
0.4
0.4
0.2
0.2
0
BUD/FORM
BUD
FORM
1.9
1.8
1.6
1.4
*
2.0
PL
Szafranski
Calverley
BUD/FORM
1,4*
1,4(*)
BUD
1,6
1,6
FORM
1,8
1,9
PL
1,9
1,8
1. Szafranski W et al. Eur Respir J 2003; 21: 74-81;
2. Calverley PM et al. Eur Respir J 2003; 22: 912-919
1.8
1.6
1.4
0
BUD/FORM
BUD
FORM
Numero medio di
riacutizzazioni/paziente/anno1
Trattamento
*
*p<0,05 vs BUD/FORM
(*)p<0,05 vs BUD/FORM
PL
(exacerbations/patient/year)
Exacerbation rate
1,2
Rate ratio (RR) = 0.74 (CI: 0.69, 0.79)
p < 0.0001
1,09
1,0
0,8
0,80
0,6
0,4
0,2
0,0
BUD/FORM
FLU/SAL
Larsson et al. J Intern Med 2013; 273(6): 584–94.
0.4
62% reduction in rate of exacerbation*
Ratio: 0.38 (95% CI: 0.25–0.57)
P < 0.001
Bud/form + TIO
PBO + TIO
Exacerbations/patient
0.3
0.2
0.1
0.0
0
15
30
45
60
75
90
Days since randomisation
Welte T, et al. Am J Respir Crit Care Med 2009;
COPD Exacerbations (Moderate or Severe)
M2-124 & M2-125 pooled analysis
 = - 17%
(CI -25;-8)
p = 0.0003
1.5
1
0.5
1.374
1.142
0
placebo
roflumilast 500µg
Calverley PMA, Rabe, KF ,et al. Lancet 2009;374:685–94
Roflumilast as Add-On Therapy in COPD
Pre-bronchodilator FEV1
1.6
Salmeterol+ Roflumilast
1.5
1.4
Salmeterol + Placebo
466
467
455
463
410
437
0
4
8
389
419
374
403
359
384
18
24
1.3
12
Weeks
Roflumilast
Placebo
Fabbri LM, Calverley PMA et al. Lancet 2009;374:695–703
Roflumilast as Add-On Therapy in COPD
Pre-bronchodilator FEV1
1.7
Tiotropium+ Roflumilast
1.6
1.5
Tiotropium + Placebo
1.4
371
372
364
363
343
352
0
4
8
325
350
12
Weeks
318
347
310
333
18
24
Roflumilast
Placebo
Fabbri LM, Calverley PMA et al. Lancet 2009;374:695–703
Phenotypes – an operational definition
‘‘a single or combination of disease attributes that
describe differences between individuals with
COPD as they relate to clinically meaningful
outcomes (symptoms, exacerbations, response to
therapy, rate of disease progression, or death).’’
Han KM, et al. Am J Respir Crit Care Med 2010; 182, 598-564
No
exacerbator
Overlap
COPD-asthma
Exacerbator with
emphysema
Exacerbator
with chronic
bronchitis
Long acting bronchodilators
Inhaled corticosteroids
Mucolytics
PDE4 inhibitors
Macrolides
M Miravitlles, et al. Eur Resp J 2013
• Cessazione dal fumo : riduzione del declino funzionale
• Vaccinazione antiinfluenzale : riduzione del 39% delle ospedalizzazioni e 50%
della mortalità
• Vaccinazione antipneumococcica: non chiara diminuzione delle riacutizzazioni;
diminuzione delle polmoniti
• Educazione all’autogestione con piano scritto
• Terapia farmacologica
• Non vi sono evidenze sull’utilizzo profilattico degli antibiotici
• La riabilitazione respiratoria è associata ad un minor numero di riacutizzazioni